The overall goal of The Clinical Profile of Parkinson's Disease (PD) Pathology, is to characterize the clinical profile of PD pathology in older person's without a diagnosis of PD. Showing that PD pathology is associated with a distinct and progressive condition among persons without a clinical diagnosis of PD, would have a transformative effect on PD studies. Although, PD only affects up to 5% of persons by age 85, compelling preliminary data shows that indices of PD pathology including nigral degeneration and Lewy bodies are present in nearly 20% of older persons without PD and are associated with the severity of parkinsonism proximate to death. This suggests that PD pathology is common and causes clinical signs in persons who do not meet clinical criteria for PD. Like the recent reclassification of AD, PD may also have an asymptomatic PD pathology phase, followed by a stage in which PD pathology results in mild motor and non-motor impairments not severe enough to warrant a diagnosis of PD, and a clinical diagnosis of PD is a later stage of the disease. Toward this end, we will apply a similar approach to that which has succeeded in transforming our ideas of AD. The proposed study will take advantage of two ongoing cohort studies, the Rush Religious Orders Study (P30AG10161) and the Memory and Aging Project (R01AG17917), whose participants have all agreed to annual clinical examination and organ donation at the time of death. Focusing on adults without clinical PD, we propose to delineate the extent and burden of PD pathology in both brain and spinal cord. Next, we propose to determine the associations of a wide range of motor and non- motor behaviors to PD pathology. Finally, we propose to develop a clinical profile for the detection of PD pathology with high sensitivity and specificity. This proposal offers the potential to greatly expand our knowledge of the clinical phase of PD and to identify people with PD for early intervention prior to overt clinial disease. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to characterize the clinical profile of Parkinson's disease (PD) pathology in older person's without a diagnosis of PD. Showing that PD pathology is associated with a distinct and progressive condition among persons without a clinical diagnosis of PD, would have a transformative effect on PD studies, in terms of potential biomarkers, early detection and interventions to delay the onset of PD.